rs8192587

chr6-32220936-C-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_004557.4(NOTCH4):c.799+42G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0236 in 1,595,952 control chromosomes in the GnomAD database, including 548 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.020 (46 hom., cov: 33)
  • Exomes 𝑓: 0.024 (502 hom.)
• Consequence: NOTCH4 NM_004557.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.450

Genes affected

NOTCH4 (HGNC:7884): (notch receptor 4) This gene encodes a member of the NOTCH family of proteins. Members of this Type I transmembrane protein family share structural characteristics including an extracellular domain consisting of multiple epidermal growth factor-like (EGF) repeats, and an intracellular domain consisting of multiple different domain types. Notch signaling is an evolutionarily conserved intercellular signaling pathway that regulates interactions between physically adjacent cells through binding of Notch family receptors to their cognate ligands. The encoded preproprotein is proteolytically processed in the trans-Golgi network to generate two polypeptide chains that heterodimerize to form the mature cell-surface receptor. This receptor may play a role in vascular, renal and hepatic development. Mutations in this gene may be associated with schizophrenia. Alternative splicing results in multiple transcript variants, at least one of which encodes an isoform that is proteolytically processed. [provided by RefSeq, Jan 2016]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0197 (3004/152304) while in subpopulation SAS AF= 0.0313 (151/4828). AF 95% confidence interval is 0.0272. There are 46 homozygotes in gnomad4. There are 1531 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd at 3006 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NOTCH4	NM_004557.4	c.799+42G>C		intron_variant		ENST00000375023.3
NOTCH4	NR_134949.2	n.938+42G>C		intron_variant, non_coding_transcript_variant
NOTCH4	NR_134950.2	n.938+42G>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NOTCH4	ENST00000375023.3	c.799+42G>C		intron_variant		1	NM_004557.4	P1
NOTCH4	ENST00000473562.1	n.928+42G>C		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes AF: 0.0198 AC: 3006 AN: 152186 Hom.: 46 Cov.: 33

Gnomad AFR AF: 0.00369

Gnomad AMI AF: 0.00440

Gnomad AMR AF: 0.0213

Gnomad ASJ AF: 0.0357

Gnomad EAS AF: 0.00406

Gnomad SAS AF: 0.0315

Gnomad FIN AF: 0.0357

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0262

Gnomad OTH AF: 0.0296

GnomAD3 exomes AF: 0.0251 AC: 5931 AN: 236178 Hom.: 119 AF XY: 0.0270 AC XY: 3431 AN XY: 127288

Gnomad AFR exome AF: 0.00319

Gnomad AMR exome AF: 0.0151

Gnomad ASJ exome AF: 0.0404

Gnomad EAS exome AF: 0.00482

Gnomad SAS exome AF: 0.0354

Gnomad FIN exome AF: 0.0379

Gnomad NFE exome AF: 0.0287

Gnomad OTH exome AF: 0.0252

GnomAD4 exome AF: 0.0240 AC: 34638 AN: 1443648 Hom.: 502 Cov.: 52 AF XY: 0.0247 AC XY: 17668 AN XY: 716024

Gnomad4 AFR exome AF: 0.00320

Gnomad4 AMR exome AF: 0.0155

Gnomad4 ASJ exome AF: 0.0364

Gnomad4 EAS exome AF: 0.00570

Gnomad4 SAS exome AF: 0.0339

Gnomad4 FIN exome AF: 0.0380

Gnomad4 NFE exome AF: 0.0240

Gnomad4 OTH exome AF: 0.0241

GnomAD4 genome AF: 0.0197 AC: 3004 AN: 152304 Hom.: 46 Cov.: 33 AF XY: 0.0206 AC XY: 1531 AN XY: 74464

Gnomad4 AFR AF: 0.00368

Gnomad4 AMR AF: 0.0212

Gnomad4 ASJ AF: 0.0357

Gnomad4 EAS AF: 0.00407

Gnomad4 SAS AF: 0.0313

Gnomad4 FIN AF: 0.0357

Gnomad4 NFE AF: 0.0262

Gnomad4 OTH AF: 0.0293

Alfa AF: 0.0239 Hom.: 13

Bravo AF: 0.0176

Asia WGS AF: 0.00953 AC: 33 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
Cadd	Benign	8.6
Dann	Benign	0.59

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.17		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs8192587; hg19: chr6-32188713; COSMIC: COSV66680083;